The present invention pertains generally to a method for treating the vessel of a patient. More specifically, the present invention pertains to a medical method for treating a vessel of a patient""s cardiovascular system by injecting a fluid directly into the vessel wall. The present invention is particularly, but not exclusively, useful for preventing a restenosis by releasing a medicament at several predetermined locations within the vessel wall to circumferentially disperse the medicament in the vessel wall.
Angioplasty is a widely used procedure for treating a stenosis within a body vessel such as a human artery. During an angioplasty procedure, a medical catheter having an inflatable balloon attached to a catheter shaft is advanced within the lumen of the body vessel until the balloon is adjacent to the stenosis. Next, the balloon is inflated causing the stenosis to compress into the vessel wall and the lumen of the vessel to dilate.
Although the angioplasty procedure is generally successful in dilating the lumen of the vessel and thereby allowing increased blood flow through the vessel, often times a restenosis occurs soon after the angioplasty procedure. It is widely recognized that the bodies response (inflammation) to tissue damage that occurs during the angioplasty procedure contributes to the restenosis. Several medicaments are known to be efficacious in the prevention of a restenosis if properly delivered near the site of the inflammation.
Heretofore, a number of devices have been suggested for use in conjunction with an angioplasty procedure to obviate a restenosis. For example, one such device utilizes a balloon to position a plurality of apertures against the vessel wall near the stenosis. After positioning the apertures, a medicament is released from the apertures, where the medicament contacts the endothelium layer of the vessel. Unfortunately, use of the aperture device generally results in an insufficient amount of medicament being delivered to the target area because a large portion of the released medicament does not penetrate the vessel wall, but rather, is washed away into the blood stream. Further, due to the toxic nature of some of the medicaments used in this procedure, the large portion of medicament entering the bloodstream can cause adverse health effects to the patient.
Also heretofore, devices capable of penetrating the wall of a vessel with a dispenser and releasing a medicament within the vessel wall have been disclosed. For example, U.S. Pat. No. 5,713,863, filed on Jan. 11, 1996 and entitled xe2x80x9cCatheter With Fluid Medication Dispensersxe2x80x9d and which is assigned to the same assignee of the present invention, discloses such a device.
It is to be appreciated that the use of devices with expanding members and penetrating dispensers will cause some trauma to the vessel wall. Specifically, as indicated above, dilation of the vessel lumen with a balloon or other expanding member is generally known to cause tissue injury to the vessel wall. Further, penetration of the vessel wall with a dispenser will certainly cause some injury to vessel wall tissue. Finally, the release of a medicament within the vessel wall will also cause some injury to the tissue of the vessel wall.
These various forms of tissue injury will trigger an inflammation response. As indicated above, this inflammation response is widely recognized to contribute to the restenosis of the vessel. It is also known that this inflammation response will cause localized changes near the injured tissue including increased permeability and increased blood flow. This localized increase in blood flow and permeability will generally increase the dispersion rate of medicaments released near an injury in a vessel wall.
For a medicament to be effective in preventing a restenosis it must be delivered to a prescribed area and in a prescribed dosage. As indicated above, the size, shape and location of the prescribed treatment area is dependent on the amount and location of tissue injury. On the other hand, the amount of tissue injury is dependent on a number of factors including the size of the balloon, the number of penetrating dispensers and the amount of medicament released. Further, the dispersion rate of the medicament will be affected by the amount of inflammation, the type of medicament, and the amount of medicament released. Consequently, all of these factors must be considered when determining the arrangement of the dispensers and the amount of medicament to be released at each dispenser that will result in a uniform dispersion of medication at the prescribed treatment area.
In light of the above, it is an object of the present invention to provide a method useful for preventing a restenosis caused by trauma to vessel tissue from an intravascular procedure. It is another object of the present invention to provide a method for preventing a restenosis in a vessel by delivering a medicament at predetermined locations within the vessel wall for dispersion into a prescribed shape that takes advantage of the increased medicinal dispersion rate due to the localized inflammation created by the procedure. It is yet another object of the present invention to prevent a restenosis by delivering a medicament at predetermined locations within a vessel wall to create a circumferential dispersion of the medicament within the vessel wall near a stenosis. Another object of the present invention is to safely deliver dangerous medicaments into a vessel wall while minimizing the amount of medicament which is washed away into the blood stream. Still another object of the present invention is to provide a method for treating a vessel which is easy to perform, safe, relatively simple, and inexpensive to perform.
The present invention is directed to a method for preventing a restenosis from occurring near the site of an intervascular catheter procedure such as a balloon angioplasty procedure. In accordance with the present method, the restenosis is prevented by medicating a prescribed treatment area within the vessel wall near the site of the angioplasty procedure. For the present method, a medicament known to prevent restenosis is delivered at predetermined locations within the vessel wall and allowed to subsequently disperse thereby medicating the prescribed treatment area. The delivery of the medicament can be accomplished either during the angioplasty procedure or shortly thereafter.
In accordance with the present method, first, the shape, size and location of the treatment area to be medicated is prescribed. For purposes of the present invention, the treatment area is generally a circumferentially shaped volume (or annulus) within the vessel wall near the site of the catheter procedure. For angioplasty procedures that dilate the lumen of the vessel near an existing stenosis, the present method contemplates medication of an annulus near the treated stenosis having a annulus length of approximately the size of the stenosis. Further, the prescribed annulus is preferably wholly contained within a particular vessel layer. For example, in the case of an arterial vessel, the particular vessel layer may be the intima or the media. Next, the delivery locations, delivery rates and delivery amounts are calculated after considering the dispersion rate of the medicament and the various factors that affect the dispersion rate such as the effect of inflammation. Once the delivery locations, rates and amounts are determined, the arrangement and size of the medicament dispensers can be determined and used to configure a catheter for delivering the medicament.
To deliver the medicament in accordance with the present method, a catheter with an expanding member, such as a balloon, is advanced along a catheter shaft within the lumen of a body vessel until the expanding member is located adjacent to the prescribed treatment area. A plurality of dispensers are mounted on the expanding member and an extracorporeal mechanism for pumping a medicinal fluid to the dispensers through a lumen in the catheter is provided. Importantly, in order to medicate an annulus within the vessel wall as contemplated by the present method, all of the dispensers are positioned on the expanding member in a plane oriented substantially perpendicular to the axis of the catheter shaft.
Once the expanding member is positioned adjacent to the treatment area, it can be activated to force the dispensers into the vessel wall. By the proper design and dimension of the expanding member and dispensers, the dispensers can be made to penetrate to the prescribed vessel layer. Once the dispensers have penetrated the vessel wall to the proper depth, a medicament can be selectively pumped through each dispenser for release at the predetermined locations. Preferably, the dispensers create a plurality of equally spaced localized medicinal deliveries which subsequently disperse to substantially medicate an annulus within the vessel wall. Simultaneously, the expanding member, which may be a balloon, can dilate the lumen of the vessel, thereby producing results similar to the balloon angioplasty procedure described above.
As provided below, the expanding member selectively and accurately controls the movement of the dispensers, and the medicament source selectively provides a pressurized supply of medicament to the dispensers. Thus, the expanding member mechanism which causes the dispensers to penetrate the vessel wall operates independently from the extracorporeal mechanism for pumping the medicinal fluid to the dispensers, thereby allowing greater freedom in medicinal delivery.
For the method of the present invention, the expanding member may include a balloon which is expandable from a contracted, first configuration to an expanded, second configuration. Preferably, the dispensers extend radially from the balloon and move with the balloon between the first configuration and the second configuration. This structure allows the dispensers to penetrate into a prescribed target vessel layer such as the intima or media for selective release of a medicament when the balloon is at the second configuration. When properly designed, this structure allows both the depth of penetration of the dispensers into the vessel wall and the force used to penetrate the vessel wall to be precisely controlled.
Further, for the method of the present invention, at least one fluid passageway provides for fluid communication between the medicament source and the dispensers. For example, the fluid passageway can include a flexible tubular sleeve which substantially encompasses and encloses at least a portion of an outer surface of the balloon. The medicament source can also include an extracorporeal fluid pump which is in fluid communication with the fluid passageway for selectively providing a pressurized supply of medicament from the medicament source to the dispensers.
Each dispenser can be a substantially tubular protrusion having an attachment end and a penetrating section for penetrating the wall of the vessel. The attachment end includes a base plate which mounts directly onto the tubular sleeve. In some of the devices disclosed herein for use in the present method, an open edge defines the penetrating section of the dispenser. In alternative devices useful for the present method and disclosed herein, each dispenser can include a porous section or an opening through the dispenser wall which defines the penetrating section.
Depending upon the medicament and the desired treatment, the medicament can be released while the dispenser penetrates the treatment area or there can be a time delay between the dispenser penetration and the release of the medicament from the dispensers.
An alternative structure for the expanding member may include a multilumen catheter, a grommet, a plurality of flexible tubes which connect the grommet to the catheter and a dispenser secured to each of the flexible tubes. The grommet is movable relative to the catheter to reposition the flexible tubes near the vessel wall.
Various medicaments can be used in the method of the present invention depending on the needs of the individual patient. As indicated above, a medicament suitable for the treatment of a stenosis or disease de novo, inhibiting a restenosis by minimizing the effects of a previous intravascular procedure and/or inhibiting a stenosis in a vessel may be used. For example, to inhibit a restenosis, the medicament may contain an anti-proliferative agent which inhibits the proliferation of smooth muscle cell growth in a vessel under certain pathological conditions. Further, medicaments which selectively kill rapidly dividing cells can also be used to inhibit the proliferation of smooth tissue growth. Other suitable medicaments can include anti-proliferative agents such as methotrexate, prednisone, adriamycin, mitomycin C, protein synthesis inhibitors, toxin fragments such as pseudomonas exotoxin (PE) or Ricin A (RA) Toxin, and radioactive isotopes such as 111Indium, 90Yttrium, 67Gallium, 99 mTc(Technetium 99), 205Thallium, and 32P(Phosphorous 32) radiopharmaceuticals. Alternatively, a medicament which stimulates the production of collateral vessels can be delivered to the target area by the present method. This provides preventative treatment for the patient by creating new collateral vessels in the event the original vessel develops a stenosis. A medicament which includes an angiogenis factor can be utilized for this purpose.
In order to decrease the amount of medicament washed away into the blood stream, a portion of the medicament could precipitate at approximately the vessel pH level of the vessel. Typically, the vessel pH is approximately 7. Thus, a medicament having a pH level of less than approximately 6 or greater than approximately 8 can be utilized. After the medicament is dispensed into the wall of the vessel, the medicament pH level approaches 7 and a portion of the medicament precipitates. For these purposes, the fluid can include a precipitator, an active component attached to or included within the precipitator and a carrier component which carries the precipitator and the active component. The precipitator precipitates in the wall of the vessel while the carrier component gets washed away into the blood stream. Because the active component is attached to or included within the precipitator, the active component of the fluid remains in the vessel wall. This minimizes the amount of the active component of the fluid medicament which is washed away into the blood stream. For these purposes, the active component of the medicament, for example, can include an anti-proliferative agent as discussed above. Alternatively, the precipitator and active component, for example, can include a radionuclide or radiopharmaceutical precipitate, such as gold colloidal, i.e. 198Au and 199Au, and/or an inorganic precipitate.
Additionally, the active component of the medicament can be designed to have a slow, time-release formulation so that the active component is released to the vessel wall over an extended period of time. Stated another way, the active component can biodegrade slowly over a period of time to gradually release the active component of the medicament into the vessel wall. A biodegradable polymer could be used to provide a control release formulation to the active component.
Alternatively, the medicament could include a binder secured to the active component of the medicament. The binder binds, attaches or crosslinks to at least a portion of the wall of the vessel. The binder can include a ligand which binds to a portion of the vessel wall such as collagen or the smooth muscle cell component of the vessel wall. This ensures that the bulk of the active component of the medicament remains in the vessel wall and minimizes the amount of the active component of the medicament which is washed away into the blood stream. Examples of ligands binding to the vessel wall components include PDGF receptors, adhesive molecules including but not limited to certain molecules of the integrin family, and receptors on activated platelets such as thrombin receptors. Alternatively, for example, phoshporous tridentate which binds to collagen can be utilized. Further, a binder that has a direct affinity to form ionic bonds, covalent bonds or Van der Waal attractions to the wall of the vessel or some component thereof can be used in the method of the present invention.
Further, a medicament for performing gene therapy on the vessel wall can be used. For example, the medicament could include either retroviral, adenoviral vectors or Adenovirus Associated Vectors (AAV) carrying the appropriate DNA payload for appropriate gene switching. The method of the present invention also allows for the use of medicaments which genetically alter the specific treatment site of the vessel without effecting the rest of the body. Additionally, the method of the present invention may be used to inject radioactive isotopes directly into the vessel wall.